Drug designers working on therapeutics against multiple sclerosis should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study in the journal Cell Reports.

In multiple sclerosis, immune cells degrade the insulation that protects neurons and allows them to signal to one another, but little is known about how immune cells penetrate the blood-brain barrier to get to neurons. Researchers have uncovered two different ways immune cells gain access to neurons and wreak their havoc.

While researchers have known that two different kinds of immune cells, Th1 and Th17 lymphocytes, are involved in degrading myelin around neurons in multiple sclerosis, they didn't know exactly how these cells crossed the blood-brain barrier to access neurons.

The blood-brain barrier is a bit of a misnomer. It not only protects the brain, but also the spine, and refers to the fact that blood vessels that supply the brain and spine are virtually impermeable because the cells that make up those blood vessels -- called endothelial cells -- are bolted tightly together by protein complexes called tight junctions. This prevents certain chemicals, harmful microbes and cells that circulate in the blood from gaining access to the brain and spine. In blood vessels that supply other organs of the body, endothelial cells are more loosely bound to one another and the connections can be adjusted to allow for the exchange of molecules and cells from the bloodstream into tissues and vice versa.

To explore how Th1 and Th17 immune cells gain access to neurons in multiple sclerosis, researchers looked at the blood-brain barrier in mice with experimental autoimmune encephalomyelitis -- a mouse version of multiple sclerosis.

They genetically labeled blood vessel endothelial cell tight junctions with a fluorescent protein to examine if and how tight junctions are involved in autoimmune encephalomyelitis in vivo in their mice. The researchers observed that the tight junctions were significantly deteriorated in the presence of Th17 cells, and that this took place early in the onset of disease.

Approximately three days later in the disease process, they found that Th1 cells were accessing and degrading myelin and neurons -- but these cells did not pass through tight junctions like the Th17 cells did. Instead, the circulating Th1 cells got to neurons by going through the blood vessel endothelial cells using specialized cell membrane structures called caveolae.

Caveolae are small pits or "caves" found on the surface of many cell types and help facilitate the passage of various molecules and cells into and/or through cells. In mice with autoimmune encephalomyelitis bred to lack caveolae, the researchers found almost no Th1 cells in the brain and spinal cord. They determined that caveolae on endothelial cells that make up blood vessels are required to help ferry Th1 cells through the blood-brain barrier.

"This is the first time we have ever seen, in live animals in real-time, the different means by which these two cell types gain access to myelin and nerves," said the senior author. "Now that we know how these cells get to neurons, drugs or small molecules can be designed that interfere with or block each of these processes to help treat and possibly prevent multiple sclerosis."